Lats1/2 Differentially Modulate the Proliferative State of Dental Epithelial Progenitors and Ameloblasts in the...

Yes-Associated Protein (YAP) is a critical regulator of cell proliferation and differentiation, having the capacity to convert differentiated cells into somatic stem cells in several contexts. Here we investigate the plasticity of adult mouse dental epithelial cells by testing the effects of ectopic YAP activation in dental epithelial progenitors and differentiated ameloblasts during incisor renewal.

Using mice with dental epithelial deletion of Lats1 and Lats2, which encode negative regulators of YAP, we assessed how ectopic YAP activation altered tissue structure, cell proliferation, and differentiation via histological analysis, EdU/BrdU labeling, and immunostaining. We also treated primary dental epithelial cells in 3D culture with TRULI, a LATS inhibitor, to test cell plasticity outside the context of an intact tissue.

YAP overactivation in the incisor epithelium induced ectopic cell proliferation in the apical bud and prolonged the proliferative state of dental epithelial progenitors, leading to a thickened suprabasal layer. However, ameloblasts remained non-proliferative. Tissue structures and differentiation of pre-ameloblasts were disrupted. Finally, LATS inhibition was able to induce colony formation in some dissociated, 3D-cultured ameloblasts.

YAP activation promotes the expansion of dental epithelial progenitors but not ameloblasts in vivo, suggesting irreversible differentiation during tooth renewal. However, when dissociated, some ameloblasts acquire plasticity. This offers a strategy to manipulate proliferation in dental epithelial cells under different conditions and may have broader applications in orthodontics, where a modular control of progenitors and differentiated cells is critical for ensuring safe stem cell-based treatments.